Overview

This trial is active, not recruiting.

Conditions advanced or metastatic breast cancer,, er+ve advanced or metastatic breast cancer.
Treatments azd5363 when combined with weekly paclitaxel., azd5363when combined with weekly paclitaxel., a placebo in combination with weekly paclitaxel.
Phase phase 1/phase 2
Sponsor AstraZeneca
Start date October 2012
End date January 2017
Trial size 140 participants
Trial identifier NCT01625286, 2011-006312-31, D3610C00002

Summary

The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer, including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) tumour mutation.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Experimental)
See intervention description below.
azd5363 when combined with weekly paclitaxel.
AZD5363: oral capsule, twice daily in a weekly 2 days on-treatment, 5 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
(Experimental)
See intervention description below.
azd5363 when combined with weekly paclitaxel.
AZD5363: oral capsule, twice daily in a weekly 4 days on-treatment, 3 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
(Active Comparator)
See intervention description below.
azd5363when combined with weekly paclitaxel.
Either a 2/5 or 3/4 intermittent dosing schedule of AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
(Placebo Comparator)
See intervention description below.
a placebo in combination with weekly paclitaxel.
Either a 2/5 or 3/4 intermittent dosing schedule of placebo matched to AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. placebo and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.

Primary Outcomes

Measure
Part A: Safety and tolerability of AZD5363 when combined with paclitaxel, in terms of numbers of patients with adverse events and serious adverse events.
time frame: Adverse events and toxicities recorded from patient screening to first of: date of withdrawal from study, date of death or date of patient completion of study. Average participation approximately 18 weeks.
Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of progression-free survival.
time frame: Tumour assessments by RECIST at screening and at 12 weekly intervals until first of: date of first documented progression, date of study withdrawal or date of death. Average participation approximately 18 weeks.

Secondary Outcomes

Measure
Part A: Preliminary anti-tumour activity of AZD5363 when combined with paclitaxel, by assessment of overall response rate (ORR) and percentage of patients without progressive disease at 12 weeks.
time frame: Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy.
Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of ORR at 12 weeks, best objective response (BOR) and durable response rate (DDR).
time frame: Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy (ORR) and first of: date of first documented progression, date of study withdrawal or date of death. Average participation approximately 18 weeks.
Part B: Relative anti-tumour activity of AZD5363, compared to placebo, when combined with paclitaxel, by comparison of change in tumouir size at 12 weeks.
time frame: Tumour assessment by RECIST at screening and at 12 weeks after date of start of study therapy.
Part B: Safety and tolerability of AZD5363 when combined with paclitaxel,in terms of numbers of patients with adverse events and serious adverse events.
time frame: Adverse events and toxicities recorded from patient screening to first of: date of study withdrawal, date of death or 28 days after date of discontinuation of all study therapies. Average participation approximately 24 weeks.
Part B: Effect on patient's quality of life (QoL) due to receipt of AZD5363 when combined with paclitaxel, by assessing changes from baseline score in a patient-completed QoL questionnaire (EORTC QLQ-30 / BR-23).
time frame: QoL questionnaires completed at screening and at 12 weekly intervals from screening until first of: date of study withdrawal, date of death or date of discontinuation of all study therapies. Average participation approximately 24 weeks.
Parts A and B: Assessment of the plasma concentration profile of AZD5363 when combined with paclitaxel.
time frame: AZD5363 plasma concentration samples will be collected during the first treatment cycle on: Part A days 2, 3, 5, 9, 16 and 23, and Part B days 2, 9 and 16, from date of start of study therapy.
Parts A and B: Assessment of the plasma concentration (PK) profile of paclitaxel alone and when combined with AZD5363.
time frame: Paclitaxel plasma concentration samples will be collected during the first treatment cycle on: Part A days 1, 2, 9, and 16, and Part B days 1 and 2, from date of start of study therapy.
Parts A and B: Assessment of the pharmacokinetic/pharmacodynamic relationship between plasma concentration of AZD5363 and plasma concentrations of pharmacodynamic biomarkers and correlation with anti-tumour activity.
time frame: PD samples will be collected on:Part A days 1,2,3,5,9,16,23; Part B days 1,2,16 from therapy start & day 1 of each cycle. PK sampling & anti-tumour activity assessment timepoints are as decribed previously. Average participation approximately 18 weeks.
Part B: Overall survival of patients treated with AZD5363, compared to placebo, when in combination with paclitaxel by assessment of time to death.
time frame: First of: date of study withdrawal or date of death. Average participation approximately 52 weeks.
Part A&B:To assess the toxicity burden associated with diarrhoea in relation to the number and duration of episodes and variations in intensity within episodes of the event's occurrence.
time frame: Time Frame: Adverse events and toxicities recorded from patient screening to first of: date of study withdrawal, date of death or 28 days after date of discontinuation of all study therapies. Average participation approximately 24 weeks

Eligibility Criteria

Female participants from 18 years up to 130 years old.

Inclusion Criteria: - Provision of informed consent. - Female patient. - Aged at least 18 years. - Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B). - World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks. Exclusion Criteria: - Clinically significant abnormalities of glucose metabolism. - Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids). - Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV. - Any prior exposure to agents which inhibit AKT as the primary pharmacological activity. - Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer. Part B: any prior chemotherapy for advanced or metastatic breast cancer.

Additional Information

Official title A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status
Description This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment is given in 28-day cycles, comprising three weeks on-therapy followed by one week off-therapy. The study will be conducted in two parts: Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4 days per week) of AZD5363 given in combination with weekly paclitaxel. The study population is female patients, 18 years or older, with advanced or metastatic breast cancer. The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to take forward to study Part B in combination with weekly paclitaxel. Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a recommended dose in each of the schedules. A total of 6 patients must be evaluated at a selected dose level for it to be confirmed as the recommended dose. All dose evaluations and recommendations will be conducted by a Safety Review Committee. Part A Patients will undergo assessments up to to withdrawal from the study or to discontinuation of study therapy. Part B. A minimum of 100 patients will be recruited to this Phase II double-blind, placebo-controlled, stratified and randomised evaluation of two treatment regimens: AZD5363 (at a dose selected and schedule from Part A) in combination with weekly paclitaxel vs. weekly paclitaxel plus placebo. The study population is female patients with Estrogen Receptor Positive advanced or metastatic breast cancer; of which approximately 50 will have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation. Part B patients will be stratified by PIK3CA tumour mutation status as: tumour mutation positive or tumour mutation not-detected. Under each stratum patients will be randomised to receive either paclitaxel + AZD5363 or paclitaxel + placebo. The purpose of Part B is to assess relative efficacy of both active and placebo regimens by comparison of: progression-free survival, overall survival, tumour response, safety and tolerability in the overall ER+ve advanced or metastatic breast cancer population, and in a subgroup of these patients with the PIK3CA tumour mutation. Patient safety and therapy tolerability will be monitored by an independent Safety Review Committee throuighout the course of Part B. Part B patients will be followed for assessment of overall survival, or to withdrawal from the study.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by AstraZeneca.